Ahmed-2018-Tumour microenvironment and metabol.pdf

Contents lists available at ScienceDirectSeminars in Cancer Biologyjournal homepage: microenvironment and metabolic plasticity in cancer and cancerstem cells:Perspectives on metabolic and immune regulatory signatures inchemoresistant ovarian cancer stem cellsNuzhat Ahmeda,b,c,d,Ruth Escalonaa,c,d,Dilys Leunga,Emily Chand,George Kannourakisa,baFiona Elsey Cancer Research Institute,Ballarat,Victoria,3353,AustraliabFederation University Australia,Ballarat,Victoria,3010,AustraliacThe Hudson Institute of Medical Research,Victoria,3168,AustraliadDepartment of Obstetrics and Gynaecology,University of Melbourne,Victoria,3052,AustraliaA R T I C L E I N F OKeywords:Ovarian carcinomaTumour cellsCancer stem cellsAscitesChemoresistanceImmune cellsCancer-associated fibroblastsEndothelial cellsA B S T R A C TCancer stem cells(CSCs)are a sub-population of tumour cells,which are responsible to drive tumour growth,metastasis and therapy resistance.It has recently been proposed that enhanced glucose metabolism and immuneevasion by tumour cells are linked,and are modulated by the changing tumour microenvironment(TME)thatcreates a competition for nutrient consumption between tumour and different sub-types of cells attracted to theTME.To facilitate efficient nutrient distribution,oncogene-induced inflammatory milieu in the tumours facil-itate adaptive metabolic changes in the surrounding non-malignant cells to secrete metabolites that are used asalternative nutrient sources by the tumours to sustain its increasing energy needs for growth and anabolicfunctions.This scenario also affects CSCs residing at the primary or metastatic niches.This review summarisesrecent advances in our understanding of the metabolic phenotypes of cancer cells and CSCs and how theseprocesses are affected by the TME.We also discuss how the evolving TME modulates tumour cells and CSCs incancer progression.Using previously described proteomic and genomic platforms,ovarian cancer cell lines and amouse xenograft model we highlight the existence of metabolic and immune regulatory signatures in che-moresistant ovarian CSCs,and discuss how these processes may affect recurrence in ovarian tumours.Wepropose that progress in cancer control and eradication may depend not only on the elimination of highlychemoresistant CSCs,but also in designing novel strategies which would intervene with the tumour-promotingTME factors.1.Cancer cell metabolismCells need fuel in the form of energy for growth,division and sur-vival.In normal non-transformed cells,this is attained through theabsorption of nutrients,which are broken down in a series of reactionsthrough cytosolic glycolysis followed by mitochondrial tricarboxylicacid(TCA)cycle coupled to oxidative phosphorylation(OXPHOS).Under normoxic condition,the process of glycolysis generates twomolecules of adenosine 5-triphosphate(ATP).On the other hand,several carbon sources such as pyruvate,glutamine,fatty acids(FA),etc.are fed into the TCA cycle to generate up to 36 molecules of ATP.Hence,normal cells rely mainly on TCA cycle and OXPHOS as an effi-cient source of energy.Tumour cells on the other hand,are required toreprogram their metabolic machinery to meet the enhanced energyrequirement of cell division,increased biosynthesis of macromoleculesfor anabolic processes and tight regulation of redox status which theyprimarily do through Warburg Effect 1.The glycolytic switch toWarburg effect is mainly promoted by oncogenes and is inhibited by thepresence of tumour suppressor genes 2.In addition,tumour cellscommunicate with the neighbouring cells in TME to enhance theirmetabolic performance on top of cell autonomous metabolic pathways3.Recent literature suggests that even though the bulk of the tumourcells display dominant Warburg phenotype,most tumour cells possessintact TCA cycle and OXPHOS 4.In addition,tumour cells adapt toamino acid,lipid,FA and cholesterol metabolism for the biosynthesis ofmacromolecules for anabolic processes.https:/doi.org/10.1016/j.semcancer.2018.10.002Received 2 August 2018;Received in revised form 5 October 2018;Accepted 8 October 2018Corresponding author at:Fiona Elsey Cancer Research Institute,Suites 23,106-110 Lydiard Street South,Ballarat Technology Park Central,Ballarat 3353,Australia.E-mail address:nuzhataunimelb.edu.au(N.Ahmed).Seminars in Cancer Biology 53(2018)265281Available online 11 October 20181044-579X/2018 The Authors.Published by Elsevier Ltd.This is an open access article under the CC BY-NC-ND license(http:/creativecommons.org/licenses/BY-NC-ND/4.0/).T1.1.Oncogenic transformation and cancer cell metabolismCancer is a by-product of several oncogenic mutations or a mutationin a single driver gene and/or loss of tumour suppressor genes,in-dicating that these phenomena are related to malignant transformation2.We discuss in brief the role of some oncogenes and tumour sup-pressor genes in cellular metabolism.1.1.1.The role of p53 in cancer cell metabolismThe p53 gene,frequently mutated in human cancer,acts as a tran-scription factor and modulates several target genes involved in theregulation of cell cycle,DNA repair,apoptosis and several other me-tabolic pathways 5.Wild-type p53 gene plays a major role in cellularmetabolism and is critical in maintaining the integrity of mitochondriaand OXPHOS,as well as inhibiting glycolysis through suppression ofglucose transporter(Glut)-1 and-4 expressions 5.In addition,wild-type p53 regulates glutamine,lipid and cholesterol metabolism throughtranscriptional control of glutamine ligase synthetase-2(GLS2),sterolregulatory element-binding protein-1(SREBP-1),sirtulin 1(SIRT1),aromatase,acyl-CoA dehydrogenase family member 11(ACAD11),lipin1,malonyl-CoA-decarboxylase(MCD),dehydrogenase/reductase 3(DHR3)and caveolin-1 5,6.Hence,loss of p53 activity by mutation orreduced expression accelerates glycolysis and leads to glutamine andlipid accumulation in cancer cells,which is metabolised through TCAcycle to provide fuel for cancer progression.1.1.2.The role of PTEN in cancer cell metabolismPTEN is one of the most frequently mutated genes in human cancers7.In animal models,deletion of PTEN leads to the development ofvarious types of tumours which resembles a range of human cancersassociated with PTEN mutation,indicating its role as a tumour sup-pressor gene 8,9.A recent study demonstrated a unique isoform ofPTEN,PTEN,which induces cytochrome c oxidase activity and ATPproduction in mitochondria 10.PTEN also sustains mitochondrialclearance by directly interacting with parkin E3 ubiquitin ligase(PRKN),via mitophagy(selective removal of damaged mitochondria byautophagy)11.These observations suggest that PTEN may have aprotective role in mitochondrial biogenesis,a feature that may be lost incancer cells.1.1.3.The role of Myc in cancer cell metabolismDeregulated expression of Mycis commonly seen in 40%of allhuman cancers(www.mycancergene.org)12.Myc-transformed cellshave increased glucose and glutamine utilisation through increasedexpression of key glycolytic and glutaminolytic enzymes 13.In ad-dition,Myc activates the expression of the enzymes ATP citrate lyase(ACLY),acetyl-CoA carboxylase(ACACA),fatty acid synthase(FASN)and stearoyl-CoA desaturase(SCD),which are all involved in FAsynthesis from citrate 14.Hence,Myc regulates glycolysis,OXPHOSand FA metabolism in cancer cells.1.1.4.The role of Ras in cancer cell metabolismRas protein is mutated in multiple cancers and it activates severaleffector pathways to regulate cellular metabolism 15.K-Ras-trans-formed tumour cells use Micropinocytosis to uptake fuel from tumourmicroenvironment for growth 16.Ras-transformed cells are able touptake albumin and exogenous lipids to provide cells with TCA cycleintermediates for anabolic processes 17.In pancreatic cancer celllines and genetically engineered mouse models,oncogenic K-Ras ex-pression increased glycolysis through the activation of the Raf/Mek/Erkpathway 18.This translational activation led to hexosamine bio-synthesis pathway(HBP),a precursor needed for glycosylation,andcritical for post-translational modification that has key roles in tu-mourigenesis 19.Oncogenic K-Ras also shunts glucose and gluta-mine-derived metabolites to pentose phosphate pathway(PPP)to pro-mote ribose biosynthesis and NADPH in cancer cells 20.In anothercontext,Ras activation was shown to induce the transcription of pro-teins catalysing four key steps to enhance glycolysis in cancer cells 21.These steps are glucose import,hexokinase(HK),phosphofructokinase(PFK)and lactate export;at least one protein catalysing each of thesefour steps is consistently elevated in human tumours.1.1.5.Heterogenic metabolism in cancer cellsRecent studies in tumour cells have shown that anaerobic glycolysisin certain population of tumour cells is optional,and OXPHOS andmitochondrial respiration can occur under certain conditions 3.Tu-mour cells encounter variable oxygen levels alternating between nor-moxic and hypoxic conditions as they disseminate 22.The enhancedglycolytic flux and reduced mitochondrial activity in tumour cellsknown as Warburg Effect commonly arises due to oxygen deprivation.Subsequently,activation and stabilisation of hypoxia inducible factor-1(HIF-1),promotes the transcriptional activation of Gluts as well asother glycolytic enzymes and lactate dehydrogenase A(LDHA),whichis responsible for the conversion of lactate to pyruvate 23.There havebeen suggestions that aerobic glycolysis could bestow greater pro-liferative advantage to tumour cells and make them resistant to spon-taneous hypoxic stress 24.In addition,lactate secreted by the tumourcells is taken up by normoxic cells in a process called MetabolicSymbiosis and converted to pyruvate for oxidation by the TCA cycle.Hence,cooperation between normoxic and hypoxic cancer cells withina tumour may maximise efficient energy distribution enabling tumoursto flourish in the TME.It has been proposed that the aerobic glycolysisin tumour cells provides an advantage as it results in incomplete utili-sation of upstream intermediates of lactate,which consequently can bereshuffled towards anabolic processes for macromolecular biosynthesisrequired for the rapidly proliferating tumour cells 25.Another pos-tulation of this theory is the emergence of acid-resistant tumour phe-notypes induced by lactic acid production due to enhanced glycolysis intumour cells 23.This acid-resistant tumour population may haveacquired growth advantage enabling them unconstrained proliferationand tissue invasion 23.In this context,it has been shown that pan-creatic,neuroendocrine,breast and renal cancers treated with angio-genic inhibitors undergo regionalisation into normoxic and hypoxiczones where cells in the normoxic zones neighbouring the hypoxic areasundergo Metabolic Symbiosis to use lactate diffused from the hypoxiccells 26.Lactate utilisation under these conditions is linked to glu-tamine metabolism through lactate-derived pyruvate transamination.This reaction allows the production of alanine and-ketoglutarate(-KG)to fuel the TCA cycle,and is dependent on mammalian target ofrapamycin(mTOR)signalling pathway as combined inhibition by an-giogenic and mTOR inhibitors enables adaptation of normoxic cells toglycolytic phenotype rendering the hypoxic population devoid ofavailable glucose.On the other hand,reliance on OXPHOS rather than glycolysis hasbeen demonstrated in several tumour models including the orthotopicmouse model of human glioblastomas 27.In a subset of melanoma,melanocyte specific transcription factor(MITF)upregulated the ex-pression of peroxisome proliferator-activated receptor-coactivator-1(PGC-1),which resulted in an increased flux through TCA cycle andenhanced OXPHOS 28.PGC-1-dependent OXPHOS is crucial formaintaining the growth and survival of this subset of melanomas.Thesestudies clearly indicate that tumour cells are capable of adapting ametabolic hybrid state in which they can use glycolytic or the OXPHOSpathway depending on the availability of nutrients in TME.It shouldalso be noted that,besides glucose,mitochondria in tumour cells havethe ability to utilise a broad range of molecules such as glutamine,FAsand lipids to fuel the electron transport chain for ATP production.Forexample,FA oxidation(FAO)was used as a major energy for triplenegative breast cancer 29.Similarly,glutamine oxidation plays acritical role in energy production in multiple cancers 30.As glutamineis the most abundant amino acid in human plasma it forms an im-portant additional source of energy,especially when energy fromN.Ahmed et al.Seminars in Cancer Biology 53(2018)265281266glycolytic flux is low.1.2.Effect of TME on cancer cell metabolismTumour-associated metabolic reprograming is not limited to tumourcells but is also affected by non-malignant cells and cytokines,growthfactors,extracellular vesicles secreted by the non-malignant cells inTME 31.The non-cancer component of tumour mostly defined astumour stroma is composed of cancer-associated fibroblasts(CAFs),endothelial cells,mesenchymal stem cells MSCs;bone marrow derived(BM)or carcinoma-associated(CA-MSCs)and cells from innate andadaptive immune systems tumour-associated macrophages(TAMs),dendritic cells(DCs),myeloid-derived tumour suppressor cells(MDSCs)conventional T cells(CD4+,CD8+,regulatory T cells)and unconven-tional T cells invariant natural killer T cells(iNKT),T cells,mucosal-associated invariant T cells(MAIT)etc.,B cells,NK cells,etc.Each ofthese cellular populations has distinct effect on tumour cell metabolism.A brief overview is discussed below.1.2.1.Effect of cancer-associated fibroblasts on cancer cell metabolismPrevious studies nearly two decades ago had shown that whencancer cells were injected in nude mice in combination with culturedfibroblasts,tumour growth was significantly accelerated compared tothe growth of tumours injected in mice with cancer cells on its own,indicating that fibroblasts play a significant tumour-promoting role32,33.The autocrine and paracrine effect of CAFs on cancer cells arenow well studied 34,35.In pancreatic K-Ras-driven tumours,CAFswere shown to induce epigenetic and metabolic changes in tumour cellsfacilitating tumour progression 36,3.CAFs-derived cytokines fa-cilitated glucose uptake in breast cancer cells by increasing the ex-pression of cell membrane-bound Glut-1 transporter level 37.Recentstudies have shown that constitutive activation of certain oncogenes K-Ras,NFB,transforming growth factor-(TGF-)and/or loss of tu-mour suppressor genes(BRCA1)in tumours induced oxidative stress inneighbouring CAFs which enhanced glycolytic capacity in CAFs,re-sulting in increased production of lactate,ketones,glutamine,otheramino acids and FAs 38,39.Lactate and other metabolic fuels pro-duced by these glycolytic active CAFs were taken up by the neigh-bouring tumour cells in a process called the Reverse Warburg Effect toincrease their tumourigenic potential 38.This oncogene-driven cou-pling of CAFs with neighbo